Pancreatic exocrine function during acute exacerbation in WBN/Kob rats with spontaneous chronic pancreatitis

Summary Conclusion Pancreatic exocrine hypofunction is markedly deteriorated during acute exacerbation in a rat model with chronic pancreatitis. Background Little is known about pancreatic exocrine function during acute exacerbation in patients with chronic pancreatitis. We investigated changes in pancreatic exocrine function after inducing acute pancreatitis in an animal model of spontaneous chronic pancreatitis. Methods WBN/Kob rats with chronic pancreatitis sequentially underwent pancreatic exocrine function test 1–6 d after surgical preparation with external pancreatic fistula. We induced acute pancreatitis in another WBN/Kob rats by iv administration of cerulein at a rate of 10 μg/kg/h for 4 h 4 after surgical preparation. Pancreatic exocrine function test was undertaken in a conscious state 1 d before and after cerulein administration. Results In WBN/Kob rats not given cerulein, pancreatic exocrine function remained almost constant, at 3–6 d after surgery. Marked hyperamylasemia developed immediately after cerulein administration. After its administration, the pancreas microscopcially showed prominent intersitial edema and intracellular vacuolization of acinar cells in addition to the finding of pre-existing chronic pancreatitis. Basal and chole-cystokinin-stimulated flow rate, bicarbonate output, and protein output, which were substantially impaired 1 d before cerulein administration, were further reduced 1 d after its administration.     

Induction of acute pancreatitis by cerulein in human IL-6 gene transgenic mice

Whether acute pancreatitis induced by cerulein was aggravated in human interleukin 6 (IL-6) transgenic mice and whether a specific anti-IL-6 receptor antibody improved pancreatitis were investigated. To induce acute pancreatitis, cerulein (50 microg/kg, seven injections) with or without 1 mg/kg lipopolysaccharides (LPS) was injected intraperitoneally every hour. In some mice, a monoclonal anti-IL-6 receptor antibody was administered before the first cerulein injection. The animals were killed 1 hour after the last injection. The pancreatic wet weight induced by cerulein alone was significantly higher in IL-6 transgenic mice compared with wild-type mice, but pretreatment with a specific anti-IL-6 receptor antibody did not reduce interstitial edema. When cerulein was administered with LPS, the pancreatic wet weight increased much more than when pancreatitis was induced by cerulein alone in both genotypes, and pretreatment with the anti-IL-6 receptor antibody decreased the pancreatic edema only in human-IL-6 transgenic mice. These results suggest that anticytokine antibodies may be effective in improving acute pancreatitis.     

Evidence for a role of free radicals by synthesized scavenger, 2-octadecylascorbic acid,in cerulein-induced mouse acute pancreatitis

To define the role of free radicals and of lipid peroxide involvement during the progress of cerulein-induced acute pancreatitis in mice, we evaluated the effect of a novel free radical scavenger, 2-octadecylascorbic acid (CV-3611), on pancreatic edema formation, and the levels of serum enzymes (amylase, lipase) and of lipid peroxide in pancreatic tissue. Mice were divided into three groups: control group, intraperitoneal injection of saline only; pancreatitis group, cerulein 50 g/kg injected intraperitoneally six times at 1-hr intervals; treatment group, CV-3611 10 mg/kg subcutaneously just after intraperitoneal cerulein injection. After the cerulein injection, the degree of pancreatic edema formation, serum amylase and lipase levels, and the amount of lipid peroxide in pancreatic tissue increased significantly during the observation period of 12 hr. Treatment with CV-3611 resulted in significant reduction in pancreatic edema formation at 3.5 hr (P<0.05) and 9 hr (P<0.05), serum amylase and lipase levels at 3.5 hr (P<0.05) and 12 hr (P<0.05), and lipid peroxide levels at 3.5 hr (P<0.05), 6 hr (P<0.05) and 12 hr (P<0.05). These results indicate that a novel free radical scavenger, CV-3611, has a strong therapeutic effect during the development of acute pancreatitis and suggest that oxygenderived free radicals play an important role in the pathogenesis of acute pancreatitis.     

Protective effect of 4-hydroxy-TEMPO, a low molecular weight superoxide dismutase mimic, on free radical toxicity in experimental pancreatitis

Summary Rats develop acute pancreatitis when infused iv for 3 h with cerulein (10 μg/kg/h). Autopsies of the pancreas seen by light microscope show interstitial edema, acinar cells vacuolization, and leukocyte margination in pancreatic capillaries; under electron microscope, severe damage concerning mitochondrial and zymogen granules structures are apparent. Particularly, swelling of the mitochondria and disruption of mitochondrial cristae was observed as well as formation of large vacuoles arising from zymogen granules and liposome fusion. A significant increase of lipid hydroperoxide level in the pancreatic tissue was observed. The purpose of this study was to evaluate the effect of 4-hydroxy-TEMPO—a low-mol-wt superoxide dismutase mimic—in a rat cerulein model of acute pancreatitis, with the expectation that free radical mediated hydroperoxide formation and tissue damage may be reduced significantly. Twenty-one male Wistar rats were divided into three groups: Group 1 (n=5) served as a control and was infused iv for 3 h with physiologic saline; Group 2 (n=8) was infused iv for 3 h with cerulein 10 μg/kg/h; and Group 3 (n=8) infused iv both with cerulein and 4-hydroxy-TEMPO 22.6 mg/kg/h. Pancreatic tissue damage was quantified by measuring lipid hydroperoxide (LOOH) level, the weight of the organ, and by light and electron microscopic examination. 4-hydroxy-TEMPO penetration across cellular membrane barriers was quantified by ESR spectrometric measuremts of 4-hydroxy-TEMPO concentration in pancreatic tissue samples and pancreatic juice as well. Administering 4-hydroxy-TEMPO to rats resulted in preventing both lipid hydroperoxide formation and severe morphological damage. 4-hydroxy-TEMPO crossed cellular membrane barriers and was excreted to pancreatic juice. Infusion of 4-hydroxy-TEMPO appears to prevent pancreatic injury caused by free radicals in experimental cerulein pancreatitis.     

Cholecystokinin antagonist prevents hyperamylasemia and improves pancreatic exocrine function in cerulein-induced acute pancreatitis.

Supramaximal cerulein administration induces acute pancreatitis, which markedly impairs pancreatic secretion in conscious rats. We hypothesized that pretreatment with the potent cholecystokinin antagonist, L-364,718, improves the pancreatic secretory impairment associated with cerulein-induced acute pancreatitis. Rats were surgically prepared with gastric, duodenal, bile, and pancreatic fistulas and jugular vein catheters. On postoperative day 4, groups of rats were administered (a) L-364,718 1 mg/kg intraduodenally, (b) cerulein 5 micrograms/kg/h for 6 h intravenously, (c) L-364,718 1 mg/kg intraduodenally followed by cerulein 5 micrograms/kg/h for 6 h intravenously, and (d) safflower oil carrier intraduodenally. On postoperative day 5, we studied cholecystokinin (CCK)-stimulated pancreatic secretion. Plasma amylase was measured at the time of surgery and at the conclusion of experiments on postoperative days 4 and 5. The duodenally administered CCK antagonist had no effect, 24 h later, on CCK-evoked protein secretion and prevented the pancreatic exocrine impairment and hyperamylasemia caused by supramaximal cerulein administration. These observations suggest that cerulein-induced acute pancreatitis is mediated by a CCK-receptor mechanism.     

Failure of a potent cholecystokinin antagonist to protect against diet-induced pancreatitis in mice

The effects of a potent cholecystokinin (CCK) receptor antagonist, L-364,718, on two forms of experimental acute pancreatitis in mice were evaluated. The antagonist prevented the hyperamylasemia, pancreatic edema, and acinar cell vacuolization that followed administration of a supramaximally stimulating dose of the cholecystokinin analogue cerulein. In contrast, the same dose of L-364,718 (1 mg/kg/6 h) and an even higher dose (10 mg/kg/6 h) failed to prevent the hyperamylasemia, acinar cell necrosis, and mortality that followed administration of a choline-deficient ethionine-supplemented diet. These observations are at variance with those previously reported to follow administration of the relatively weak cholecystokinin antagonist proglumide (Niederau C et al. J Clin Invest 1986;78:1056-63). The observations reported in this communication suggest that cholecystokinin does not play an important role in diet-induced pancreatitis and that CCK receptor antagonists are unlikely to be of benefit in the treatment of clinical acute pancreatitis.     

Peptide Leukotriene Receptor Antagonist Diminishes Pancreatic Edema Formation in Rats with Cerulein-Induced Acute Pancreatitis

Background: This study was designed to evaluate the protective effect of a peptide leukotriene receptor antagonist, pranlukast hydrate, against pancreatic injuries during acute pancreatitis. Methods: Acute pancreatitis was induced in rats by intravenous infusion of a supramaximal dose of cerulein (5 μg/kg·h for 4 h). In this model marked hyperamylasemia, a significant increase in pancreatic water content, and a significant increase in pancreatic microvascular leakage of Evans blue dye were observed. Pancreatic subcellular redistribution of the lysosomal enzyme cathepsin B from the lysosomal fraction to the zymogen fraction was also observed. Results: Pretreatment with pranlukast hydrate at a dose of 10 mg/kg (twice, 8 and 4 h before cerulein infusion) significantly inhibited these pancreatic injuries, including hyperamylasemia, increased pancreatic microvascular permeability, and redistribution of cathepsin B in pancreatic acinar cells. Conclusions: These results suggest that peptide leukotrienes may be involved in the pathogenesis of acute pancreatitis in the early stage of the disease and that peptide leukotriene receptor antagonist might be of therapeutic value for treatment of acute pancreatitis.     

Effect of urinary trypsin inhibitor on pancreatic cellular and lysosomal fragility in cerulein-induced acute pancreatitis in rats

We evaluated the protective effect and the mechanism of action of the trypsin inhibitor, urinastatin, extracted from human urine, in experimental acute pancreatitis induced by a supramaximal dose of cerulein (5 g/kg/hr for 3.5 hr). Urinastatin in a dose of 10,000 units/kg/hr was given by three different methods of continuous infusion: (1) 2 hr before and during cerulein infusion, (2) only during cerulein infusion, and (3) starting 1 hr after the beginning of cerulein infusion and continued for 3.5 hr. In protocol 1 and 2 urinastatin was significantly more protective than in 3. In protocol 1 urinastatin was very protective in all parameters tested (serum amylase level, pancreatic water and amylase content, distribution of lysosomal enzymes, cellular and lysosomal fragility). These results suggest that the administration of urinastatin before and during cerulein infusion may suppress the pathogenesis and evolution of pancreatitis by inhibiting the chain reaction of pancreatic enzyme activation closely related to redistribution of lysosomal enzyme and lysosomal fragility.     

Effects of short-term pancreatic duct obstruction in rats.

The short-term effects of rat pancreatic duct obstruction were evaluated and compared with those recently reported to follow obstruction of the rabbit pancreatic duct. In both species pancreatic edema and hyperamylasemia are noted, and the lysosomal hydrolase cathepsin B is redistributed from the lysosome-enriched to the zymogen granule-enriched subcellular fraction. Theoretically, this redistribution phenomenon might lead to digestive enzyme activation because cathepsin B is known to be capable of activating trypsinogen. The hyperamylasemia and pancreatic edema (but not the cathepsin B redistribution) that follow rat pancreatic duct obstruction were increased by infusion of a submaximally stimulating dose of the cholecystokinin analogue cerulein. Administration of the cholecystokinin-receptor antagonist L-364,718 reduced the hyperamylasemia but did not alter the pancreatic edema or cathepsin B redistribution. These observations indicate that cholecystokinin may modulate some but not all of the effects of duct obstruction. Secretin administration increased the degree of pancreatic edema and had no demonstrable protective effect. The rat duct-obstruction model described in this report may prove particularly useful in future studies designed to clarify the early events underlying the development of acute pancreatitis.     

Duodenal lactoferrin in patients with chronic pancreatitis and gastrointestinal diseases

Lactoferrin (LF), chymotrypsin and lipase activity were measured in duodenal juice during pancreatic stimulation. Secretin (0.5 CU/kg/h) plus cerulein (75 ng/kg/h) were infused intravenously in 98 subjects: 33 patients without organic diseases (C), 40 patients affected by chronic pancreatitis (CP), and 25 patients with different gastrointestinal diseases (GID). LF was determined by means of a new noncompetitive immunoenzymatic assay with a sensitivity in the duodenal juice of 5 ng/ml. Duodenal LF concentrations were significantly higher in CP than in C or GID (p less than 0.001). LF was in a normal range in acute relapsing pancreatitis due to biliary stones or pancreas divisum. In the diagnosis of the chronic pancreatitis, LF/lipase ratios showed a specificity of 93% and a sensitivity of 95%. Our results show that LF immunoassay in duodenal juice is a sensitive and accurate assay to apply in pancreatic function tests involving duodenal content analysis.     

Nonesterified fatty acids in acute cerulein-induced pancreatitis in the rat are they really deleteriousin vivo?

During acute pancreatitis, experimental data obtainedin vitro suggested that pancreatic lipase generates nonesterified fatty acids (NEFA), noxious for acinar cells, by hydrolysis of pancreatic or circulating triglycerides. The purpose of this work was to determine whether experimentally induced high plasma NEFA levels do indeed aggravatein vivo cerulein-induced pancreatitis. Anesthetized Sprague-Dawley rats received cerulein and were simultaneously infused intravenously with either saline or a triglyceride + heparin mixture (TGH) in order to increase the amount of circulating NEFA. Plasma NEFA increased about fourfold (3.02±0.28 µmol/liter) in animals infused with TGH with respect to controls (0.75±0.05 µmol/liter). In rats receiving cerulein + TGH, pancreatic enzyme levels in plasma, ascites, and histological alterations of the pancreas did not differ from those observed in the rats receiving cerulein + saline. There was less macroscopic pancreatic edema (P<0.01) in the cerulein + TGH group than in the cerulein + saline group. Separate infusion of either heparin alone or of triglycerides alone had no effect. We conclude that high levels of circulating NEFA do not aggravate cerulein pancreatitis in rats and may even induce a protective effect.F.P. was the recipient of a scholarship from the Fondation pour la Recherche Médicale (Paris). Partial financial support of the work was provided by the Conseil Scientifique of Faculté X. Bichat and by Association Charles Debray.     

吡咯列酮对雨蛙肽诱导急性胰腺炎氧化应激过程的作用

目的 探讨过氧化物酶体增殖物激活受体(PPAR)γ激动剂吡咯列酮在雨蛙肽诱导大鼠急性胰腺炎中对氧化应激产物的影响及保护作用.方法 30只雄性SD大鼠随机分为对照组、雨蛙肽+不同剂量吡咯列酮组、雨蛙肽组、雨蛙肽+吡咯列酮+GW9662组.每组6只.急性胰腺炎造模30 min后处死大鼠,光镜下观察胰腺组织病理学变化,测定各组大鼠胰腺组织质量与体重比,比色法检测胰腺组织髓过氧化物酶(MPO)活性、丙二醛(MDA)和一氧化氮合酶(NOS)及组织诱导型一氧化氮合酶(iNOS)含量.结果 与对照组比较,雨蛙肽组胰腺组织水肿严重胰腺净重/体重(0.0072比0.0042)],MPO活性、MDA、NOS及iNOS含量升高(P＜0.01).与雨蛙肽组比较,吡咯列酮20 mg/kg及40 mg/kg组胰腺损伤减轻,胰腺净重/体重、MPO活性、MDA和NOS及iNOS含量降低(P＜0.05);与吡咯列酮40 mg/kg组比较,PPARγ拮抗剂GW9662逆转了吡咯列酮的保护作用(P＜0.05).结论 在雨蛙肽诱导的大鼠急性胰腺炎发病中,胰腺腺泡细胞的氧化应激损伤起了重要的作用,PPARγ激动剂吡咯列酮预先干预,通过降低氧化应激过程,对雨蛙肽诱导的大鼠急性胰腺炎有一定的保护作用.     

Role of ischemia in acute pancreatitis

Ischemia has been considered to play a role in the development of acute pancreatitis. The aim of this study was to investigate the effect of ischemia, caused by hemorrhagic shock, on cerulein-induced acute pancreatitis in rats. Acute pancreatitis was induced by the intravenous infusion of a supramaximally stimulating dose of cerulein (10 g/kg/hr) for 6 hr. Hemorrhagic shock was induced by the removal of blood until the mean arterial blood pressure reached 35 mm Hg. This level was maintained for 30 min, after which time all the blood was reinfused. Hemorrhagic shock alone induced no morphological change in the pancreas. However, after the induction of hemorrhagic shock in animals treated with cerulein, hemorrhage and parenchymal necrosis were frequently observed in the pancreas. Seven of 20 rats (35%) receiving cerulein plus hemorrhagic shock had died by 48 hr after the start of cerulein infusion, whereas none of the rats in the cerulein or shock group died during this experiment. Cathepsin B activity in the pancreas of the cerulein plus shock group was significantly higher than in the other groups at 48 hr. These results suggest that ischemia may be a contributing factor in the pathogenesis of acute pancreatitis.This study was supported by a grant, Scientific Research B-03454319, from the Ministry of Education, Science and Culture, and a grant from the Ministry of Health and Welfare of Japan     

Amelioration of rat cerulein pancreatitis by guamerin-derived peptide, a novel elastase inhibitor

Increased activity of various proteases is observed in both human and experimental pancreatitis; however, the information on the effects of specific protease inhibitors on the disease is limited. In this study we show that a novel elastase inhibitor, guamerin-derived synthetic peptide (GDSP), improves the parameters of cerulein-induced acute pancreatitis in the rat. The effects of GDSP on pancreatic weight, serum amylase and lipase, morphologic changes in the pancreas, neutrophil infiltration, and nuclear factor KB (NF-KB) activation were measured in rats infused with supramaximal dose of cerulein (5 (g/kg/h) for 6 h. The effects of GDSP were also measured on superoxide formation by activated human neutrophils. The effects of GDSP were compared with those of another elastase inhibitor, elastatinal. GDSP significantly inhibited edema formation, neutrophil infiltration, acinar cell damage, and plasma lipase and amylase increases caused by cerulein. GDSP also completely inhibited superoxide formation in the human neutrophils stimulated by N-formyl-methionine-leucine-phenyl-alanine (fMLP) or 12-O-tetradecanoylphorbol-13-acetate (TPA). Elastatinal had some of the same effects as GDSP but was less potent and effective. These results demonstrate a beneficial effect of GDSP, a novel specific elastase inhibitor, on the development of rat cerulein pancreatitis.     

Protective effects of rhubarb on experimental severe acute pancreatitis

AIM: To investigate the effects of rhubarb on severe acute pancreatitis (SAP) in rats. METHODS: Severe acute pancreatitis was induced by two intraperitoneal injections of cerulein (40 μg/kg body weight) plus 5-h restraint water-immersion stress. Rhubarb (75-150 mg/kg) was orally fed before the first cerulein injection. The degree of pancreatic edema, serum amylase level, local pancreatic blood flow (PBF), and histological alterations were investigated. The effects of rhubarb on pancreatic exocrine secretion in this model were evaluated by comparing with those of somatostatin. RESULTS: In the Cerulein+Stress group, severe edema and diffuse hemorrhage in the pancreas were observed, the pancreatic wet weight (11.60&#177;0.61 g/Kg) and serum amylase (458 490&#177;43 100 U/L) were markedly increased (P&lt;0.01 vs control). In the rhubarb (150 mg/kg) treated rats, necrosis and polymorphonuclear neutrophil (PMN) infiltration in the pancreas were significantly reduced (P&lt;0.01), and a marked decrease (50%) in serum amylase levels was also observed (P&lt;0.01). PBF dropped to 38% (93&#177;5 mL/min per 100 g) of the control in the Cerulein+Stress group and partly recovered in the Cerulein+Stress+Rhubarb 150 mg group (135&#177;12 mL/min per 100 g) (P&lt;0.01). The pancreatic exocrine function was impaired in the SAP rats. The amylase levels of pancreatic juice were reduced in the rats treated with rhubarb or somatostatin, comparing with that of untreated SAP group. The bicarbonate concentration of pancreatic juice was markedly elevated only in the rhubarbtreated group (P&lt;0.01). CONCLUSION: Rhubarb can exert protective effects on SAP, probably by inhibiting the inflammation of pancreas, improving pancreatic microcirculation, and altering exocrine secretion.     

Neutrophil elastase inhibitor (ONO-5046) prevents lung hemorrhage induced by lipopolysaccharide in rat model of cerulein pancreatitis

The protective effects of a neutrophil elastase inhibitor (ONO-5046) on cerulein-induced pancreatitis followed by a septic challenge with intraperitoneal lipopolysaccharide (LPS) were studied in a rat model. Pancreatitis was induced by four intramuscular injections of cerulein (50 μg/kg at 1-hr intervals). ONO-5046 was administered by continuous intravenous infusion via the right jugular vein (50 mg/kg/hr, 30 min prior to the first cerulein injection to 20 hr following the last cerulein injection). Significant differences in serum amylase and pancreatic wet weight ratio were not observed between the animals with pancreatitis treated with or without ONO-5046. There was no significant difference in thein vitro tumor necrosis factor-alpha (TNF-α) production by peritoneal macrophages from rats with pancreatitis treated with or without ONO-5046. In a second experiment, LPS (10 mg/kg) was administered intraperitoneally as the septic challenge 6 hr following the first cerulein injection. Lung hemorrhage was seen in the animals with pancreatitis untreated with ONO-5046 24 hr following the first cerulein injection. No significant lung hemorrhage was observed in the animals with pancreatitis treated with ONO-5046 administering 30 min prior to the first cerulein injection. These results suggest that lung hemorrhage in cerulein-induced pancreatitis that follows a septic challenge with LPS can be prevented by the intravenous administration of ONO-5046. Thus there is a significant role for neutrophil elastase in pancreatitisassociated lung injury.     

Fasting prevents acute pancreatitis induced by cerulein in rats

We examined the effect of fasting on the course of experimental acute pancreatitis induced in rats by four subcutaneous injections of 20 g/kg body weight of cerulein at hourly intervals. Rats were either fasted from 24 hr before to 9 hr after the first cerulein injection or fed ad libitumthroughout the experiment. Twenty-four hours of fasting reduced cerulein-induced increases in serum levels of amylase and anionic trypsin(ogen) to 50 and 70% of those in fed rats, respectively. Increases in pancreatic wet weight after cerulein injections were also less in fasted rats than in fed rats. Pancreatic content of trypsin was significantly decreased after a 24-hr fast, and no further changes were induced by cerulein injections. The histological signs of acute pancreatitis were greatly alleviated by fasting. However, 24 hr of fasting did not alter the sensitivity and responsiveness of the exocrine pancreas to cerulein in both in vivoand in vitro.Plasma CCK bioactivity and immunoreactive secretin concentration in 24-hr-fasted rats were significantly lower than those in fed rats. Administration of CCK receptor antagonist, loxiglumide, 12 hr prior to the induction of acute pancreatitis reduced the increase in serum amylase activity in fed rats to nearly the same levels as that in fasted rats and alleviated histological signs of pancreatitis to some extent. These present observations suggest that fasting lessens the severity of cerulein-induced acute pancreatitis by reducing endogenous CCK release.This work was supported in part by a grant from the Japanese Ministry of Health and Welfare and Grant-in-Aid for Scientific Research (C).     

Stress kinase inhibition modulates acute experimental pancreatitis

AIM: To examine the role of p38 during acute experimental cerulein pancreatitis. METHODS: Rats were treated with cerulein with or without a specific JNK inhibitor (CEP1347) and/or a specific p38 inhibitor (SB203580) and pancreatic stress kinase activity was determined. Parameters to assess pancreatitis included trypsin, amylase, lipase, pancreatic weight and histology. RESULTS: JNK inhibition with CEP1347 ameliorated pancreatitis, reducing pancreatic edema. In contrast, p38 inhibition with SB203580 aggravated pancreatitis with higher trypsin levels and, with induction of acinar necrosis not normally found after cerulein hyperstimulation. Simultaneous treatment with both CEP1347 and SB203580 mutually abolished the effects of either compound on cerulein pancreatitis. CONCLUSION: Stress kinases modulate pancreatitis differentially. JNK seems to promote pancreatitis development, possibly by supporting inflammatory reactions such as edema formation while its inhibition ameliorates pancreatitis. In contrast, p38 may help reduce organ destruction while inhibition of p38 during induction of cerulein pancreatitis leads to the occurrence of acinar necrosis.     

Effect of buprenorphine on pancreatic enzyme synthesis and secretion in normal rats and rats with acute edematous pancreatitis

Pancreatic enzyme secretion is inhibited during acute pancreatitis, resulting in an increase in acinar zymogen content. Since the premature activation of zymogens has been assigned a central role in the pathogenesis of acute pancreatitis, minimizing the amount of stored zymogens might lead to less severe acute pancreatitis. Inhibition of enzyme synthesis or stimulation of enzyme secretion would result in reduction of zymogen stores. Opiates have a varying effect on pancreatic secretion, depending on the dosage, site of administration, and presence of pancreatic stimulants. The effect of opiates and acute pancreatitis on individual pancreatic enzyme synthesis is unknown. The following study was undertaken in order to examine the effects of an opiate on pancreatic enzyme secretion and synthesis during experimental acute pancreatitis. Four groups of rats were studied. Group I received cerulein (25 µg/kg); group II received an opiate, buprenorphine (BPN, 0.5 mg/kg); and group III received cerulein and BPN. Drugs were dissolved in gelatin/saline and injected subcutaneously. A control group (group IV) received only gelatin/saline. Rats were sacrificed 4 hr after injection, and pancreatic mass was measured. Pancreatic acini were prepared and assayed for amylase and DNA content. Amylase, trypsinogen, chymotrypsinogen and lipase synthesis, and amylase secretion were measured for 2 hr. Results showed that, compared to controls, acini of rats with AP had increased amylase content, a finding consistent with decreasedin vivo amylase secretion. Total protein and individual enzyme synthesis rates were significantly lower in the acini of the rats with AP than in those of the controls. Negative feedback inhibition of enzyme synthesis due to the increased stores of intracellular enzymes may account for these findings. BPN reduced pancreatic edema in rats with acute pancreatitis (AP). Acinar amylase content of rats with AP treated with BPN was significantly lower than in acini of rats with AP. As amylase secretion was lower in the AP + BPN rats, the reduced acinar amylase content was probably solely due to the reduction in enzyme synthesis observed in the AP + BPN rats. The results suggest that BPN may have a moderating effect on the development of AP.This study was supported by a research grant from the South African Medical Research Council.     

The effect of platelet activating factor antagonist (BN 52021) on cerulein-induced acute pancreatitis with reference to oxygen radicals

Acute edematous pancreatitis was induced in Wistar male rats by iv infusion of cerulein (CR) in the dose of 5.10(-6)g.kg-1.h-1 during 3 or 6 h. The effect of BN 52021--platelet activating factor (PAF) receptor antagonist, against this model of disease was examined. BN 52021 was applied iv as a bolus injection in the dose of 5.10(-3)g.kg-1 at 0 time. Treatment with this agent significantly ameliorates cerulein-induced acute pancreatitis in rats. The effect of BN 52021 was expressed by significant reduction of pancreas edema, diminution of hyperamylasemia, lack of superoxide dismutase activity depletion, and inhibition of lipid peroxidation in pancreatic tissue. These changes were accompanied by significant reduction of acinar cells vacuolization and remarkable inhibition of infiltration with inflammatory cells in the interacinar space. We suppose that beneficial effect of BN 52021 against cerulein-induced acute pancreatitis in rats depends on the prevention of inflammatory cells activation and subsequent generation of oxygen radicals within pancreatic tissue.